NM_144573.4:c.7_9delGAT

Variant names:

• chr1-77916110-AATG-A
• rs760463744
• NM_144573.4:c.7_9delGAT

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PM4_Supporting

The NM_144573.4(NEXN):​c.7_9delGAT​(p.Asp3del) variant causes a conservative inframe deletion change. The variant allele was found at a frequency of 0.0000149 in 1,607,658 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: NEXN NM_144573.4 conservative_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 6.37
• Publications: 0 publications found

Genes affected

NEXN (HGNC:29557): (nexilin F-actin binding protein) This gene encodes a filamentous actin-binding protein that may function in cell adhesion and migration. Mutations in this gene have been associated with dilated cardiomyopathy, also known as CMD1CC. Alternatively spliced transcript variants have been described.[provided by RefSeq, Feb 2010]

NEXN Gene-Disease associations (from GenCC):

• dilated cardiomyopathy

  Inheritance: AD Classification: STRONG Submitted by: ClinGen
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• dilated cardiomyopathy 1CC

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• hypertrophic cardiomyopathy 20

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_144573.4. Strenght limited to Supporting due to length of the change: 1aa.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_144573.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEXN	NM_144573.4	MANE Select	c.7_9delGAT	p.Asp3del	conservative_inframe_deletion	Exon 2 of 13	NP_653174.3	Q0ZGT2-1
	NEXN	NM_001172309.2		c.7_9delGAT	p.Asp3del	conservative_inframe_deletion	Exon 2 of 12	NP_001165780.1	Q0ZGT2-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEXN	ENST00000334785.12	TSL:1 MANE Select	c.7_9delGAT	p.Asp3del	conservative_inframe_deletion	Exon 2 of 13	ENSP00000333938.7	Q0ZGT2-1
	NEXN	ENST00000401035.7	TSL:1	c.7_9delGAT	p.Asp3del	conservative_inframe_deletion	Exon 2 of 9	ENSP00000383814.3	E7ETM8
	NEXN	ENST00000951152.1		c.7_9delGAT	p.Asp3del	conservative_inframe_deletion	Exon 3 of 14	ENSP00000621211.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152130 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000202 AC: 5 AN: 247444 AF XY: 0.0000149

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000356

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000151 AC: 22 AN: 1455528 Hom.: 0 AF XY: 0.0000110 AC XY: 8 AN XY: 724164

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33308

American (AMR) AF: 0.0000224 AC: 1 AN: 44568

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25914

East Asian (EAS) AF: 0.00 AC: 0 AN: 39296

South Asian (SAS) AF: 0.00 AC: 0 AN: 85754

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52790

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5530

European-Non Finnish (NFE) AF: 0.0000189 AC: 21 AN: 1108358

Other (OTH) AF: 0.00 AC: 0 AN: 60010

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000127922), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152130 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74324

African (AFR) AF: 0.0000241 AC: 1 AN: 41438

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10582

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Cardiovascular phenotype (1)
-	1	-	Dilated cardiomyopathy 1CC;C3151267:Hypertrophic cardiomyopathy 20 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.4
Mutation Taster		=69/31	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs760463744; hg19: chr1-78381795;